About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

June 18, 2002

Save Your Tears

Posted by Derek

Having unloaded on the Weekly Standardlast week, I now find myself taking aim at the Wall Street Journal. Pretty soon, I'm going to be in the pundit equivalent of Albania (as was,) having ditched my every natural ally.

But it has to be done. The Journal has an editorial today on the Imclone situation - an long impassioned one that starts from false premises and draws incorrect conclusions from them. Let's excerpt the thing:

After starting off by expressing sympathy for cancer patients (and no sympathy for Sam Waksal or Martha Stewart, all perfectly defensible positions,) the editorial calls for "focusing on the FDA's role in this fiasco. . .while Imclone has not produced a study of the size and type the FDA appears to want, the larger truth is that Erbitux continues to show promising results iin small trials."

Note the "appears." Actually, it "appears" that the FDA made its requirements for clinical trials very clear, and it was Imclone that obfuscated. The dispute, which came to light during the recent congressional hearings, centers on the Phase II trial, a combination therapy of Imclone's Erbitux and the current chemotherapy agent irinotecan for colorectal cancer. Originally, as of August 1999, patients were going to get the combination of the two drugs only if their disease had still progressed after two cycles of irinotecan alone. Imclone amended this in October to allow combination therapy after any irinotecan treatment at all, and it appears that the FDA didn't completely catch on. And as it turned out, this plan muddied eventually the data thoroughly enough to make it hard to see if Imclone's drug did anything at all. But it sure did speed things up, which seems to have been what really mattered.

Harlan Waksal of Imclone maintained that they didn't mislead anyone. Minutes of a key meeting in August of 2000, though, showed that the FDA was still under the impression that the original rules applied, and no one from Imclone bothered to correct them. Even when Imclone got "Fast Track" approval in January of 2001, the FDA letter shows their decision was based on the original clinical protocol. No one from Imclone said a word.

And the "larger truth" is that small trials don't mean much. You want meaning, you run a large trial, and you run it the right way, with a design that's capable of distinguishing your drug's effects from random clinical noise. Imclone set everything up to run the fastest, cheapest trial they thought they could possibly get away with, putting the approval of their drug at risk by doing so.

Back to the editorial: "Apparently, the FDA would like Erbitux to show "single-agent activity," even though there is good reason to believe it may work better in combination with traditional chemotherapy drugs." Well, these good reasons turn out to be largely propaganda. Imclone's colorectal cancer trial, as detailed above, relied on giving Erbitux as a combination therapy. When they asked for fast-track approval status, the FDA did indeed get recommendations to turn them down, since the drug had never been tried as a stand-alone therapy. Imclone made great protestations that their drug was not effective by itself, that it had synergistic effects with irinotecan, and that it would be downright unethical to run a trial as a monotherapy. The FDA bought it, and gave them fast-track.

But the data that Imclone backed all this up with wasn't from colorectal cancer patients - it was from renal cancer, which is a very different disease. In January 2001, the FDA (feeling that they'd been had) told Imclone that they needed a monotherapy trial, which they ran. You wouldn't know that from the Journal's editorial, would you? But they ran it in the quickest, shoddiest way possible, with a total of only 57 patients. Six of them responded to Erbitux as a single therapy, but the small number of data points made the results a statistical hairball. Maybe it worked, maybe it didn't.

Sam Waksal told Bristol-Meyers Squibb that this was good news, and that the FDA was pleased with it - but the agency has no record of ever having seen the data at that point, and "pleased" wasn't the right word when it finally showed up. Remember, this study could have shown that Erbitux worked by itself, which would have surprised people after Imclone's earlier statements, but would have been strong data for approval nonetheless. Or it could have confirmed their contention that the drug wouldn't work solo. It did neither, undermining both arguments.

"Too often," the Journal says as the editorial goes into the home stretch, "the FDA simply isn't clear about what a drug like Erbitux has to do to prove itself effective. . ." On the contrary, at least in this case. The record shows that the FDA was quite clear about what it wanted, and informed Imclone in a timely manner. The record also shows that Imclone misled the FDA, their partners at Bristol-Meyers Squibb, and their stockholders at almost every opportunity.

I understand the Journal's reflexive small-government postion, and I sympathize with it most of the time. But this isn't the big regulatory agency beating up on a poor company that only wants to help sick cancer patients. This is a company with their eye on their own stock options, playing games with the data to try to get their drug through as quickly as possible. They took stupid, unacceptable risks by doing so. To use the Journal's formulation, they played these games with the health and hopes of the terminally ill. I've no sympathy for Imclone at all. No one should.